The nonepisodic, autosomal dominant, spinocerebellar ataxias (SCA) share the clinical features of progressive incoordination of gait, hand and eye movements and dysarthria, associated with degeneration of the cerebellar cortex and other regions of the central nervous system. Additional features, such as mental retardation, retinopathy, sensory neuropathy or myoclonus are found in some members of the disease family. The incidence of the disease is approximately 1 to 5/100,000, with an average age of onset in the third decade.
There are at least 20 genetically distinct autosomal dominant SCAs (see Mariotti, C., DiDonato, S., “Cerebellar/spinocerebellar syndromes,” Neurol. Sci. 22:S88-S92 (2001)). Trinucleotide repeat expansions (CAG)n, coding for polyglutamine tracts are responsible for SCA1,SCA2,SCA3,SCA6,SCA7, SCA12 and SCA17, whereas expanded CTG and ATTCT repeats are responsible for SCA8 and SCA10, respectively. In North American populations approximately 30% of SCA families are not linked to the known loci (Moseley et al., Neurology 51:1666-1671, 1998).
Given the prevalence of SCA cases not linked to any known genetic loci, there is a need to identify genetic mutations associated with the SCA syndromes that can be used in a genetic screen to identify subjects susceptible to ataxic neurological disease. The present inventors have discovered that individuals with mutations in the protein kinase C gamma (“PRKCG”) gene, coding for the protein kinase C gamma protein (“PKCγ”), display an adult onset ataxia.